The incidence of food allergies is on the rise in Western societies. Common food allergies include milk-, egg-, soy and peanut allergy, and especially the latter can be fatal. An allergic response occurs when the dietary allergen gains access to IgE molecules on the surface of Mast cells in the intestine or in other tissues. It is therefore reasonable to assume that intestinal absorption of the allergens is detrimental. However, intestinal absorption of the allergen, and of dietary antigens in general, is also required for the induction of broad systemic immunological tolerance ("oral tolerance"), which prevents food allergies and may even be used to treat food allergies. It appears thus that the mechanism of antigen absorption plays a crucial role in the pathogenesis of food allergies. Unfortunately, relatively little is currently known on the mechanism by which food antigens cross the intestinal epithelium, and how they are subsequently transported through the body. Most dietary proteins, including most known allergens, have emulsifying properties, which predicts that they show affinity for lipoprotein particles, such as chylomicrons. These large emulsion particles transport dietary long-chain triglycerides (LCT, "fat") through mesenteric lymph and blood. If dietary antigens are bound to chylomicrons, they would then be transported to chylomicron target tissues, such as mesenteric lymph nodes (MLN). Transport of dietary antigens to MLN could promote oral tolerance to the antigen, since this is the common immune response in these lymph nodes. Thus, chylomicron-dependent antigen absorption is hypothesized to promote oral tolerance. Most food staples, including those with allergens such as milk, eggs, soybeans and peanuts, also contain significant amounts of LCT, meaning that antigen ingestion is followed by chylomicron secretion. We hypothesize that intestinal absorption and systemic transport of dietary antigens occurs through association with chylomicron secretion. More specifically, we hypothesize that 1.) dietary antigens associate with newly formed chylomicron particles within intestinal epithelial cells (IEC) and are secreted into mesenteric lymph in association with nascent chylomicrons, 2.) dietary antigens are transported in association with chylomicrons through mesenteric lymph, via MLN, into blood, 3.) chylomicron-dependent antigen absorption promotes oral tolerance.These hypotheses are supported by preliminary data obtained with a prototypical food allergen, ovalbumin (OVA), in mice, but future experiments will also study peanut allergens. We propose to study the absorption mechanism in detail in this R21 grant application, and to explore immune modulating effects of the novel chylomicron pathway. These studies are expected to significantly impact food allergy research, since they define the underlying mechanism of dietary antigen absorption and provide the mechanistic framework for optimization of antigen delivery to the intestinal and peripheral immune system.